TY - JOUR
T1 - PCP effector gene Inturned is an important regulator of cilia formation and embryonic development in mammals
AU - Zeng, Huiqing
AU - Hoover, Amber N.
AU - Liu, Aimin
N1 - Funding Information:
We thank Westley Heydeck, Drs. Lee Niswander and Wendy Hanna-Rose for critically reading the manuscript. We thank Dr. Cindy Mckinney and Tom Salada at the Penn State University transgenic mouse facility for their technical help in generating the Intu mutant ES cells and chimeric mice. We thank Drs B. Wang and T. Caspary for providing antibodies against Gli3 and Arl13B; and Drs. P. Beachy, A. Joyner, M. Scott, G. Martin and D. Duboule for RNA in situ probes for Shh, Gli1, Ptch1, Fgf4, Hoxd11 and Hoxd13. The monoclonal antibodies against Shh, Nkx2.2, Isl1 and Pax7 developed by Drs. Jessell and Kawakami were obtained from the Developmental Studies Hybridoma Bank developed under the auspices of the NICHD and maintained by The University of Iowa, Department of Biological Sciences, Iowa City, IA 52242. A. L. is supported by a Penn State University new lab start-up fund and a Young Investigator Career Development Award from the PKD foundation.
PY - 2010/3/15
Y1 - 2010/3/15
N2 - The PCP effector gene Inturned regulates planar cell polarity (PCP) and wing hair formation in Drosophila wings. In order to understand the roles for Inturned in mammalian embryonic development, we generated a null mutant allele for the mouse homologue of Inturned (Intu) via gene-targeting in ES cells. Mouse Intu null mutants are homozygous lethal at midgestation, exhibiting multiple defects including neural tube closure defects, abnormal dorsal/ventral patterning of the central nervous system and abnormal anterior-posterior patterning of the limbs resulting in severe polydactyly (7-9 digits each limb). The developmental processes affected by the Intu mutation are under the control of Hh signaling through Gli-family transcription factors. We found that in Intu mutant embryos the expression of Gli1 and Ptch1, two direct transcriptional targets of Hh signaling, is down-regulated, and the proteolytic processing of Gli3 is compromised. We further demonstrate that Intu plays significant roles in the formation of primary cilia both during embryonic development and in cultured fibroblasts. Finally, a cytoplasmic GFP-Intu fusion protein efficiently rescues the ciliogenic defects in Intu mutant cells. In conclusion, we show that PCP effector gene Intu is an important regulator of cilia formation, Hh signal transduction, and embryonic development in mammals.
AB - The PCP effector gene Inturned regulates planar cell polarity (PCP) and wing hair formation in Drosophila wings. In order to understand the roles for Inturned in mammalian embryonic development, we generated a null mutant allele for the mouse homologue of Inturned (Intu) via gene-targeting in ES cells. Mouse Intu null mutants are homozygous lethal at midgestation, exhibiting multiple defects including neural tube closure defects, abnormal dorsal/ventral patterning of the central nervous system and abnormal anterior-posterior patterning of the limbs resulting in severe polydactyly (7-9 digits each limb). The developmental processes affected by the Intu mutation are under the control of Hh signaling through Gli-family transcription factors. We found that in Intu mutant embryos the expression of Gli1 and Ptch1, two direct transcriptional targets of Hh signaling, is down-regulated, and the proteolytic processing of Gli3 is compromised. We further demonstrate that Intu plays significant roles in the formation of primary cilia both during embryonic development and in cultured fibroblasts. Finally, a cytoplasmic GFP-Intu fusion protein efficiently rescues the ciliogenic defects in Intu mutant cells. In conclusion, we show that PCP effector gene Intu is an important regulator of cilia formation, Hh signal transduction, and embryonic development in mammals.
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U2 - 10.1016/j.ydbio.2010.01.003
DO - 10.1016/j.ydbio.2010.01.003
M3 - Article
C2 - 20067783
AN - SCOPUS:77149146791
SN - 0012-1606
VL - 339
SP - 418
EP - 428
JO - Developmental biology
JF - Developmental biology
IS - 2
ER -